Mutation of CERKL, a Novel Human Ceramide Kinase Gene, Causes Autosomal Recessive Retinitis Pigmentosa (RP26) Miquel Tuson, Gemma Marfany, Roser Gonzàlez-Duarte

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Mutation of CERKL, a Novel Human Ceramide Kinase Gene, Causes Autosomal Recessive Retinitis Pigmentosa (RP26) Miquel Tuson, Gemma Marfany, Roser Gonzàlez-Duarte The American Journal of Human Genetics Volume 74, Issue 1, Pages 128-138 (January 2004) DOI: 10.1086/381055 Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 1 The RP26 locus and the CERKL gene and protein. A, RP26 physical map of the 12.5-Mb cosegregation interval between markers D2S2261 and D2S273. B, Localization of CERKL within the candidate region (“CR”) defined by homozygosity mapping. Genes (rectangles) and the transcription direction (arrowheads) are indicated. C, CERKL exon/intron structure. The location of the R275X null mutation in exon 5 is shown. The American Journal of Human Genetics 2004 74, 128-138DOI: (10.1086/381055) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 2 Protein alignment of human (“h”) and murine (“m”) CERKL and CERK. Identical residues are highlighted in black, and conservative positions are in gray. The solid black line underlines the conserved COG1597 (LCB5) domain detected after comparison with the NCBI Conserved Domain Database. Murine CERKL sequence was assembled from GenBank sequences BY742285 and BC046474, human CERK sequence from AB079066, and murine CERK sequence from AB79067. The American Journal of Human Genetics 2004 74, 128-138DOI: (10.1086/381055) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 3 Unrooted phylogenetic tree of several members of the diacylglycerol, sphingosine, and ceramide kinases, including the human and murine CERKL sequences described in the present study (boxed). The tree was obtained with the neighbor-joining algorithm of the program ClustalX version 1.64b. Numbers show the values for the bootstrap analysis. SPHKs = sphingosine kinases; CERKs = ceramide kinases; and DGKs = diacylglycerol kinases. Abbreviations and GenBank accession numbers are as follows: human sphingosine kinase 1 (hSPHK1), AAF73423; murine sphingosine kinase 1 (mSPHK1), AAC61697; human sphingosine kinase 2 (hSPHK2), AAF74124; murine sphingosine kinase 2 (mSPHK2), AAF74125; Drosophila sphingosine kinase (dSPHK), AAF48045; Ciona intestinalis sphingosine kinase (ciSPHK), AK112588; yeast sphingosine kinase Lcb4 (Lcb4p), NP_014814; yeast sphingosine kinase Lcb5 (Lcb5p), NP_013361; Arabidopsis thaliana sphingosine kinase (AtSPHK), AY128394; human ceramide kinase (hCERK), AB079066; murine ceramide kinase (mCERK), AB079067; Ciona intestinalis ceramide kinase (ciCERK), AK112750; Drosophila ceramide kinase (dCERK), AAF52040; human ceramide kinase-like (hCERKL), AY357073; murine ceramide kinase-like (mCERKL), BY742285 and BC046474; Caenorhabditis elegans ceramide kinase (cCERK), AAC67466; human diacylglycerol kinase β subunit (hDGKb), Q9Y6T7; murine diacylglycerol kinase β subunit (mDGKb), XP_147651; human diacylglycerol kinase epsilon subunit (hDGKe), NP_003638; murine diacylglycerol kinase epsilon subunit (mDGKe), NP_062378); Caenorhabditis elegans diacylglycerol kinase 1 (cDGK1), NP_508190; Arabidopsis thaliana diacylglycerol kinase 1 (AtDGK1), Q39017; Drosophila diacylglycerol kinase 2 (dDGK2), Q09103; and Drosophila diacylglycerol kinase 1 (dDGK1), Q01583. The American Journal of Human Genetics 2004 74, 128-138DOI: (10.1086/381055) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 4 A, DNA sequence of exon 5 in an unaffected individual and patient VI.15 of the P2 family, showing the homozygous nonsense R257X mutation. B, Pedigrees of P2 and E1 families, showing the ARMS analysis of R257X mutation. A specific primer was designed to generate an AvaII restriction site in the amplified wild-type allele. All RP-affected individuals are homozygous for the mutant, nonrestricted allele. Individuals whose DNA samples were not available are indicated by a number sign (#). The American Journal of Human Genetics 2004 74, 128-138DOI: (10.1086/381055) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 5 CERKL and GAPD (control) RT-PCR expression analysis on several human tissues, including retina The American Journal of Human Genetics 2004 74, 128-138DOI: (10.1086/381055) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 6 A, Cerkl in situ hybridization on murine eye sections with the antisense riboprobe. B, Cerkl in situ hybridization on murine eye sections with the sense riboprobe (negative control). C, Rhodopsin in situ hybridization on murine eye sections (positive control). RPE = retinal pigment epithelium; PhR = photoreceptor cell layer; ONL = outer nuclear layer; OPL = outer plexiform layer; INL = inner nuclear layer; IPL = inner plexiform layer; GCL = ganglion cell layer. The American Journal of Human Genetics 2004 74, 128-138DOI: (10.1086/381055) Copyright © 2004 The American Society of Human Genetics Terms and Conditions